Glaucoma is a leading cause of blindness affecting approximately 3 million people in the United States. About one-third of the patient population afflicted with glaucoma suffers from what is known as low tension glaucoma. R. Weinreb, Eye Research Seminar, Research to Prevent Blindness, (1990) p. 14-15. This type of glaucoma is not associated with elevated intraocular pressure (IOP). However, antiglaucoma agents are generally designed to lower the IOP in order to improve the ocular blood flow, particularly at the choroid, retina and lamina cribosa of the optic nerve. Such antiglaucoma agents are ineffective for the treatment of low tension glaucoma, as the IOP of these patients is already low. Therefore most low tension glaucoma patients undergo a filtering operation instead of being treated with antiglaucoma drugs. Chandler et al. Glaucoma, Lea & Febiger, Philadelphia, 111-115 (1965).
Ischemic retinal degeneration, or degeneration of the central part of the retina, is the second leading cause of blindness among people of all ages. It causes at least some loss of vision in 10 million people over the age of 50. Lierman, Building a Healthy America, Mary Ann Liebert Inc., New York 115-119 (1987). This ischemic retinal degeneration is caused by various diseases, including diabetic retinopathy, glaucoma, sickle cell retinopathy, vascular abnormalities, obstructive arterial and venous retinopathies, venous capillary insufficiency, hypertensive retinopathy, inflammation, tumors, retinal detachment, etc. U.S. Dept of Health & Human Services, Vision Research, Report of Retinal and Choroid Diseases Panel, NIH Publication #83-2471 (1983). LeVail et al., Retinal Degeneration, Experimental and Clinical Studies, Alan R. Liss Inc., New York (1985).
The retina is supplied with oxygen and nutrients by two vascular systems, one within the retina itself (central retinal artery) and one in the choroid (posterior ciliary artery). Interruption or impairment of either system leads to degeneration of the retina and ultimately to loss of vision. There are many diseases and conditions that affect retinal circulation and nutritional supply. Early improvement in blood flow or nutrient supply to the retina in some of these diseases and throughout the time course of others might be the key to slowing vision loss or eliminating it altogether.
Various dopamine antagonists have been shown to lower IOP. U.S. Pat. Nos. 4,565,821 and 4,772,616 describe the use of butypherones (i.e. haloperidol, trifluperidol and moperone) and domperidone to lower intraocular pressure. U.S. Pat. No. 4,521,414 describes the use of the R isomer of timolol as an anti-hypertensive agent for the eye. The use of the dopamine antagonists haloperidol, moperone, trifluperidol, clofluperol, pipamperone and lemperone in the treatment of ocular hypertension and glaucoma is also described. Chiou, Ophthal. Res. 16:129-134 (1984).
Although the foregoing references describe the use of dopamine antagonists to decrease IOP, Chiou et al., J. Ocular Pharmacy, 5:281-292 (1989) found that some dopamine antagonists increase IOP as well. Chiou et al. hypothesized that dopamine antagonists may decrease ciliary blood flow at post-synaptic sites in order to lower the IOP and improve ocular blood flow.
It has also been shown that all dopamine antagonists do not act on ocular blood flow uniformly. For example, haloperidol, moperone and trifluperidol were found to reduce the blood flow to the retina and choroid. Chiou et al., Ophthal. Res. 18:265-269 (1986), and Yan et al. Ophthal. Res. 19:45-48 (1987). Although domperidone was found to increase the retinal blood flow, it also caused eye irritation.